Breast cancer is known as the second leading cause of cancer deaths among women in the United States[1],[2]. Depending on the stage of the cancer, treatment generally includes surgery, radiation, and/ or chemotherapy[3]. The biggest drawbacks with these treatment options, however, is that surgery is invasive, while chemotherapy is systemic and critically affects patients as chemotherapeutic drugs kill both cancer cells and fast-growing healthy cells. Unfortunately, 20% of women cleared of the disease experience a recurrence within ten years of their initial treatment[1]. Targeted drug delivery is one way in which treatment could be improved and made more effective by targeting more of the intended and residual cancer cells following tumor removal, while sparing healthy cells. Polymeric nanoparticles can be functionalized with targeting modalities such as peptides[4][5]. This project aims to improve the delivery of chemotherapeutic drugs for the treatment of breast cancer by not only including a targeting peptide identified through phage display, but also a pH responsive linkage for more selectivity (as cancerous tumors are found to be more acidic compared to healthy tissues[6]-[8]). Finally, test these particles in a novel transgenic mouse tumor model, which has an intact immune system.
Polyethylene glycol (PEG)-Poly(lactic-co-glycolic) acid (PLGA) nanoparticles have been fabricated and loaded with the chemotherapeutic drug Doxorubicin conjugated to the core of the particles[9]. Using thiol-ene click chemistry[10],[11], an eight amino acid targeting peptide was attached to the particles. This peptide was identified through phage display as being specific for the SKBR-3 human breast cancer cell line[12],[13], which overexpresses the HER2 gene[14]. Early in vitro experiments showed that the peptide was approximately twice as effective at targeting and killing SKBR-3 cells compared to a control cell line. The particles were then tested in a mouse breast cancer model for human HER2+ breast cancer. This model is established by inoculating mouse mammary tumor cells with the human wild-type gene HER2 into C57BL/6 HER2 transgenic mice[15]. Particles with and without the targeting peptide were injected through the mouse lateral tail vein. Using FITC to label the peptide, the targeting peptide could be tracked and the localization in the tumor tissue was seen. Overall the transgenic mice received particles and all survived. Particles with pH responsive acetal crosslinking in the core are currently being developed and tested[16],[17]. It is expected that this stronger hydrophobic core will allow for more drug loading, and more importantly, more specific release in the more acidic tumor tissue.
The therapeutic efficacies of a drug is improved by releasing it from a targeted polymer-drug system as the drug should better target and kill cancer cells in this case, while more healthy cells are spared from the harsh drugs. The superior transgenic model used confirms that this is possible.
References:
[1] “Breast Cancer Home Page - National Cancer Institute.” [Online]. Available: http://www.cancer.gov/cancertopics/types/breast. [Accessed: 20-Aug-2015].
[2] Ma, J. & Jemal, A. Breast Cancer Metastasis and Drug Resistance. (2013). doi:10.1007/978-1-4614-5647-6
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[12] Abbineni, G. & Modali, S. Evolutionary Selection new breast cancer cell-targeting peptides and phages with the cell-targeting peptides fully displayed on the major coat and their effects on actin dynamics during cell internalization. Mol. … 7, 1629–1642 (2010).
[13] Gandra, N. et al. Bacteriophage bionanowire as a carrier for both cancer-targeting peptides and photosensitizers and its use in selective cancer cell killing by photodynamic therapy. Small 9, 215–21 (2013).
[14] Gee, M., Upadhyay, R. & Bergquist, H. Human Breast Cancer Tumor Models: Molecular Imaging of Drug Susceptibility and Dosing during HER2/neu-targeted Therapy 1. Radiology 248, 925–935 (2008).
[15] Wang, S. H. et al. Characterization of a Novel Transgenic Mouse Tumor Model for Targeting HER2 + Cancer Stem Cells. Int. J. Biol. Sci. 10, 25–32 (2014).
[16] Bachelder, E. M., Beaudette, T. T., Broaders, K. E., Dashe, J. & Fre, J. M. J. Acetal-Derivatized Dextran : An Acid-Responsive Biodegradable Material for Therapeutic Applications. JACS Commun. 130, 10494–10495 (2008).
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